Metabolic Regulation of Cancer Cell Response to Radiation Therapy

Abstract

CD31 immunofluoresence staining was performed on tumor sections to measure endothelial cell area. Results: Among miRs targeting SMPD1, miR-15a exhibited the greatest differential change in HUVECs at 6 hours post-IR between low and high dose radiation. Lower dose was associated with higher miR-15a and vice versa. Exogenous miR-15a mimic significantly decreased SMPD1 mRNA and protein expression. miR-15a levels were reciprocal in magnitude to SMPD1 mRNA levels. miR-15a inhibition decreased cell proliferation in both HUVECs and CT26 colorectal cells and increased apoptosis when combined with radiation. Associated with increased apoptosis, miR-15a inhibition significantly increased Fas expression in HUVECs compared to radiation alone. Further, miR-15a inhibition increased inflammasomeassociated caspase 1, GSDMD expression, and inflammatory CXCL10 production. Both systemic and vascular targeted delivery of miR-15a inhibitor significantly diminished tumor growth and decreased endothelial cell density in vivo in our CRC flank tumor model. Conclusion: Acting upon the vasculature, our data demonstrates miR-15a inhibition increases SMPD1 in ECs, decreases proliferation in vitro and in vivo, and stimulates pyroptosis to abrogate tumor growth.